Quaternized nicotinium derivatives



United States Patent r 2,890,222 QUA'IERNIZED NICOTINHIM DERIVATIVESGeorge M. Omietanski, Tonawanda, N. assignor to The Ohio StateUniversity Research Foundation, Co= :lumbus, Ohio No Drawing.Application March 14, 1958 Serial No. 721,333

6 Claims. (Cl. 260-491) As shown in the structural formula, nicotine is2-(3- pyridyl)-1-methylpyrrolidine, a weak base because of the twotertiary amines present in the molecule. The pyrrolidine nitrogen reactslike an aliphatic tertiary amine while the other nitrogen is part of anaromatic ring system (pyridine) and exhibits markedly differentbehavior. As expected, salts of nicotine are readily converted back tothe free base on treatment with aqueous sodium hydroxide. Naturallyoccurring nicotine is levorotatory (carbon 2 of the pyrrolidine ring isasymmetric); but a discussion of stereoisomeric possibilities is notrequired for a proper understanding of this invention.

It has been discovered recently that chloramine andhydroxylamine-o-sulfonic acid react with trisubstituted tertiary aminesto give the corresponding trisubstituted hydrazinium chlorides andsulfates (or bisulfates) respectively. The bisulfate product fromnicotine and hydroxylamine-o -sulfonic .acid, for example, may beformulated in either of two equivalent ways.

l H804- and E so.- \N on, NH; \N H, NH, 2

23,893,222 Patented June 9, 1959 "ice In the above formula, X may be theanion of an inorganic acid. Suitable anions are chloride, bromide,iodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate, diacidphosphate, etc. The chloride is most conveniently prepared by bubblingchloramine into a solution of nicotine in an inert solvent such aschloroform. The bisulfate'is best prepared by the reaction ofhydroxylamine-o-sulfonic acid and nicotine in a hydroxylic solvent suchas methyl alcohol. Introduction of the other anions of this invention isby metathesis. While several basic rnetathetical approaches areavailable, the method selected depends on experimental convenience, costof reagents and the differences in physical properties between theproduct and the starting material to be utilized. Reaction ofl-aminonicotinium chloride with a soluble silver salt, such as silvernitrate, results in the precipitation of silver chloride and theformation of l-aminonicotinium nitrate. In an analogous fashion,treatment of the sulfate with a barium salt results in the precipitationof barium sulfate and conversion to the anion of the barium salt. Goingfrom a more soluble l-aminonicotiniurn salt to a less soluble one isbest accomplished by treating the former with a solution containing anexcess of the anion being introduced. Another technique, which isindependent of the formation of an insoluble solid, is to react thechloride with an excess of the desired anion as its acid; hydrogenchloride is evolved as the new salt is formed.

The salts of my novel l-aminonicotinium compounds are useful as improvedinsecticides, parasiticides, and fungicides. My compounds are usefulwhere nicotine is useful but are superior to and more convenient to usethan nicotine itself because they are less toxic to warmblooded animalsby inhalation or absorption through the skin. The increased stability ofmy novel compounds over nicotine is extended to salts of nicotine. Forexample, l-aminonicotinium compounds are stable to alkali and resistoxidation as evidenced by their failure to discolor and turn brown inair.

The scope and utility of the present invention is further illustrated bythe following examples.

, Example I Hydroxylamine-o-sulfonic acid was made according to thedirections of Sommer, Schulz and Nassau, Z. Anorg. u. Allgem. Cherrr,147, 142 (1925 Titration with acidified potassium iodide solution showedit to contain up to 97% active material. A methyl alcohol solutioncontaining 26 g. of hydroxylamine-o-sulfonic acid was added gradually to16 g. of nicotine in 50 ml. of methanol saturated with solid sodiumhydroxide; a vigorous reaction resulted. After refluxing four hours, thereaction mixture was filtered hot and the precipitate washed withadditional solvent till free of strong reducing agent. The residueobtained from the evaporation of the combined filtrate and washings wasdissolved in water, made Ten ml. of water containing 0.5 g. of theproduct of Example I and 0.5 g. of ammonium silicate was evaporated todryness on the steam bath and kept there for three additional hours. .Asolution of 1 ml. of concentrated hydrochloric :acid and 2 ml. of'waterwas added with stirring and the system again evaporated. The resultantl-aminonicotinium .polysilieate on silica was washed with water andvacuum dried. ,The product was an off-white powder that darkened ca. 150.C. but did not melt.

Example .111

Using the chloramine generator described in US. Patent 2,710,248, 50 g.of nicotine in-one liter of chloroform was treated with a 100% excess of--chloramine. After standing overnight, the reaction mixture wasfiltered from about .g. of ammonium chloride and evaporated to .give adarkbrown viscous-material. The residue was taken up in isopropylalcohol, filtered and the solvent evaporated leaving the semi-solidalcoholate which was dissolved in water and made alkaline tophenolphthalein by the addition of sodium carbonate. The aqueoussolution .was treatedwith charcoal, filtered, extracted twice with equalvolumes of ether, extracted once with an equal volume of benzene andevaporated in vacuo to give back l-aminonicotinium-chloride isopropylalcohol (calculated for chloride 12.85% found on titration, 12.63%).Heating to'7580 C. drove off the alcohol leaving the noncrystalline,light brown l-aminonicotinium chloride which started decomposing ca. 150C.

Example IV A 50 mg. portion of the brown alcoholate of Example III wasdissolvedin water, treated with charcoal, filtered and poured into a tenvolume excess of-dioxane. After the resultant solid had settled, thesolvent was decanted and the solid washed by decantation with two 5 ml.portions of dioxane and washed free of dioxane by trituration withether. The addition of 50 mg. of sulfuric acid in 5 ml. of isopropylalcohol resulted in the formation of a slightly yellow gum. Extractionof this gum with methyl alcohol gave two products, one solvent solubleand a trace of insoluble material as the other. Evaporation of thealcohol gave the major product, ,l-aminonicotinium sulfate, as ayellowish gum soluble in Water and methyl alcohol but insoluble inisopropyl alcohol. It decomposed ca. 145-148 C., gave an immediateprecipitate with barium ion but was not converted to nicotine ontreatment with strong aqueous sodium hydroxide.

. of chloramine. The reaction mixture, kept at 05 C Example V A mg.portion of the alcoholate of Example 111 was purified as described inthe previous example. A solution of 300 mg. of phosphoric acid in 10 ml.of ether was added with stirring to the previously ether-washed residue.On standing, the yellow residue changed to a white solid. The productwas soluble in Water and methanol, insoluble in isopropyl alcohol anddioxane, and decomposed with darkening and gas evolution above 200 C.Since its aqueous solutions were acidic, the product has been assignedthe diacid phosphate structure.

Example VI Using -the chloramine generator described in US. Patent2,710,248, 42 g. of nicotine (no solvent) in a bubbler tube was treatedwith half the theoretical amount set up to a honey-combed elf-whitesolid-showing very little obvious brown liquid. Trituration of thereaction mixture with benzene gave l-aminonicotinium chloride, as anoif-white solid, so hygroscopic that it immediately turned to a yellowgel in air. Using this material in place of the product of Example .111(the alcoholate) in the procedure of Example IV gave the same yellowgummy mixture.

Example VII A small sample of l-aminonicotinium chloride, as prepared-inthe previous example, 'was treated with alcoholic silver nitrate. Thereaction mixture was filtered from the resultant silver chloride andevaporated in vacuo. The-resultant l-aminonicotinium nitrate was athick, heat unstable'oil.

-I claim:

1. New chemical compounds having the general formula:

- (3 pyridyl)pyrrolidinium No references cited.

1. NEW CHEMICAL COMPOUNDS HAVING THE GENERAL FORMULA: